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系統識別號 U0026-0902201113472500
論文名稱(中文) 探討紫檀芪在肺癌化學預防的角色和機轉
論文名稱(英文) The roles and mechanisms of pterostilbene in lung cancer chemoprevention
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 99
學期 1
出版年 100
研究生(中文) 蔡尚杰
研究生(英文) Shang-Jie Tsai
學號 s7697408
學位類別 碩士
語文別 中文
論文頁數 75頁
口試委員 指導教授-王應然
召集委員-何其儻
口試委員-何元順
口試委員-潘敏雄
口試委員-施能耀
中文關鍵字 紫檀芪  細胞凋亡  自體吞噬  p53  A/J小鼠 
英文關鍵字 pterostilbene  apoptosis  autophagy  p53  A/J mice 
學科別分類
中文摘要 肺癌是全球癌症死亡最主要的原因。雖然現在的醫療設備無論是檢測上或是治療上都有很大的進展,但是肺癌病患五年內的存活率仍然低於15%,因此有關於研究肺癌預防或是治療策略有其重要性。紫檀芪最先從紫檀木 (P. santa-linus) 中發現並分離出來。目前紫檀芪已經被證實出具有多種藥理活性包含抗氧化、抗菌、降血脂以及抗癌的活性。而本次研究的目的主要是利用人類肺癌細胞株和化學物誘發肺腫瘤的動物實驗來探討紫檀芪可能的抗癌效果。在細胞實驗當中,使用了H460 (p53野生型) 和H1299 (p53 不表現型) 的人類肺癌細胞株來進行實驗,利用MTT試驗觀察細胞的存活率。細胞週期的分佈、細胞凋亡和自體吞噬的比例則利用流式細胞儀分析。利用螢光顯微鏡和電子顯微鏡觀察細胞凋亡和自體吞噬的型態,此外使用西方墨點法來觀察相關細胞週期、細胞凋亡和自體吞噬的相關蛋白表現。在動物實驗當中,利用urethane誘發A/J肺腫瘤的小鼠模式來探討紫檀芪對於肺腫瘤的化學預防效果。結果發現,在H460和H1299細胞中,紫檀芪能夠抑制兩株細胞的生長、細胞週期進行並且誘導細胞凋亡和自體吞噬。在誘導細胞凋亡方面H460細胞程度較高。相反的,自體吞噬的程度H1299細胞較高。紫檀芪能夠透過抑制AKT的活性並且活化AMP-activated kinase (AMPK)、JNK來促進自體吞噬。此外在H460細胞中能透過AMPK/p53路徑來促進細胞凋亡。動物實驗方面,雖然紫檀芪無法有效抑制腫瘤的發生率,但能夠降低腫瘤的多發性、體積以及肺腫瘤負荷量。這些抑制的效果可能跟促進細胞凋亡、自體吞噬以及抑制增生有關。綜合以上結果,紫檀芪能夠抑制p53野生型和p53不表現型的肺癌細胞生長,並且在A/J小鼠動物實驗當中降低肺腫瘤多發性。根據這些實驗結果指出紫檀芪有很大的潛力應用在人類肺癌的化學預防以及治療上。
英文摘要 Lung cancer is the major cause of cancer deaths in the world. Despite new advancement has been made in lung cnacer diagnosis or therapy, the overall 5-year survival rate is still less than 15%. Thus, there is a need to investigate the strategies for lung cancer prevention and therapy. Pterostilbene was first isolated from P. santa-linus (red sandalwood), and has been shown diverse pharmacologic activities including antioxidation, antidiabetic, hypolipidemic and anticancer activities. The objective of this study is to investigate the possible anti-cancer and chemoprevention effects of pterostilbene in human lung cancer cell lines and chemical-induced lung tumorigenesis animal model. In in vitro study, H460 (p53 wild type) and H1299 (p53 null) were used. Cell viability was examined by MTT assay. Cell cycle distribution, apoptosis, and autophagy were measured by flow cytometry. Cell morphology of autophagy and apoptosis were observed by fluorescence microscopy and electron microscopy. The expression of proteins that regulated cell cycle, apoptosis and autophagy were analyzed by Western blotting. In in vivo study, the lung tumor chemoprevention efficiency of pterostilbene was evaluated by urethane-induced lung tumorigenesis in A/J mice model. The results showed that pterostilbene suppressed cell growth, cell cycle progression, induced apoptosis and autophagy in both cells. It induced higher apoptosis level in H460 cells compared with H1299 cells. On the contrary, the level of autophagy was higher in H1299 cells. Pterostilbene could inhibit AKT activity, activate AMP-activated kinase (AMPK), JNK activity to induce autophagy. In addition, it could induce apoptosis through AMPK/p53 pathway in H460 cells. In animal study, pterostilbene couldn’t suppress lung tumor incidence but decrease tumor multiplicity, volume and burden. These effects were associated with enhanced apoptosis, autophagy and suppressed proliferation. Taken together, pterostilbene could suppress the growth in both p53 wild type and p53 null lung cancer cells and decrease lung tumorigenesis in A/J mice model. These results indicated that pterostilbene may have a potential to serve as a chemopreventive and therapeutic agent for human lung cancer.
論文目次 第一章、序論 1
第二章、文獻回顧 2
第一節、肺癌 (Lung Cancer) 目前診斷以及治療 2
第二節、化學預防 (Chemoprevention) 3
第三節、紫檀芪 (Pterostilbene) 4
第四節、細胞凋亡 (Apoptosis) 5
第五節、自體吞噬 (Autophagy) 8
第六節、AMPK (AMP-activated protein kinase) 9
第七節、Urethane誘發A/J小鼠肺腫瘤之動物實驗模式 11
第三章、研究目的 13
第四章、研究架構 14
第一節、細胞實驗架構 14
第二節、動物實驗架構 15
第五章、研究材料與方法 17
第一節 研究材料 17
(一) 常用試劑 17
(二) 常用儀器 18
(三) 常用溶液 19
第二節 研究方法 21
(一) 人類肺癌細胞培養以及培養液 (medium) 製備 21
(二) 細胞解凍 21
(三) 細胞培養 22
(四) 細胞冷凍 22
(五) Trypan blue dye exclusion assay:細胞計數 23
(六) MTT assay 23
(七) 西方墨點法 (Western blotting) 24
(八) 細胞週期 (Cell Cycle) 分析 26
(九) 粒線體膜電位 membrane potential (ΔΨm) 分析 27
(十) 細胞自體吞噬 (Autophagy) 分析 27
(十一) 細胞凋亡 (apoptosis) 分析 28
(十二) Agarose gel electrophorese 28
(十三) 螢光顯微鏡分析自體吞噬 (Autophagy) 現象 29
(十四) 螢光顯微鏡分析細胞微核現象 (micronuclei formation) 30
(十五) 電子顯微鏡 30
(十六) 動物實驗 31
(十七) 蘇木紫伊紅染色 (Hematoxylin & Eosin Staining) 33
(十八) 免疫組織染色 (Immunohistochemistry) 33
(十九) 統計分析 35
第六章、實驗結果 36
第一節、紫檀芪對於人類肺癌細胞H460、H1299的劑量效應 36
第二節、紫檀芪對於H460、H1299細胞的細胞週期分佈影響 36
第三節、紫檀芪的處理對於人類肺癌細胞H460、H1299細胞凋亡的現象 37
第四節、觀察紫檀芪對於H460和H1299細胞產生自體吞噬的影響 39
第五節、紫檀芪對於人類肺癌細胞之訊息路徑相關蛋白表現的影響 40
第六節、觀察A/J小鼠肺腫瘤誘發動物實驗中紫檀芪的影響 41
第七節、觀察在動物實驗中紫檀芪所影響的細胞凋亡和自體吞噬現象 43
第七章、討論 44
第八章、結論及建議 50
第九章、文獻參考 51
圖 表 59
補充資料 73

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